The disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands, agonists and partial agonists for the mGluR2 PAM receptor and may be useful for the treatment of various disorders of the central nervous system.
Glutamate is the major excitatory neurotransmitter in the mammalian brain, playing an important physiological role in a wide variety of processes. Glutamatergic neurotransmission is predominantly mediated through activation of cell surface receptors including ligand-gated ion channels (ionotropic receptors) and metabotropic glutamate G protein coupled receptors (mGluRs). The metabotropic glutamate receptor family is comprised of 8 family members that are part of the family 3 GPCR superfamily. These receptors are further subdivided into Group I (mGluR 1, 5), Group II (mGluR 2, 3) and Group III (mGluR 4, 6, 7, 8) based upon sequence homology, receptor signaling, and pharmacology.
At the cellular level, mGluR2 plays a key role as an autoreceptor in glutamate terminals, though it is generally thought to be localized at the periphery of the synapse, away from the active zone. Activation of the mGluR2 receptor by glutamate or other orthosteric ligands results in a reduction of adenylate cyclase via a Gai protein and a subsequent reduction of glutamate release from the pre-synaptic terminal. mGluR2 receptors are localized to regions of the brain involved with psychiatric disorders, including the prefrontal cortex, striatum, hippocampus, and amygdala. Excessive glutamate release has been hypothesized to contribute to the underlying pathophysiology in both anxiety and schizophrenia; therefore, activators of mGluR2 receptors may offer therapeutic benefits in these disorders. This biological phenomenon was demonstrated pre-clinically in a study by Moghaddam and Adams (1998) in which they treated rats with phencyclidine (PCP), an NMDA receptor blocker, and detected increased glutamate release in the mPFC and striatum of these animals as well as hyper-locomotion and working memory deficits. The mGluR2/3 agonist, LY-354740, lowered brain glutamate levels and reversed the behavioral effects of PCP. Many more studies have demonstrated efficacy in a variety of pre-clinical models of psychosis and anxiety with mGluR2/3 agonists. Such pre-clinical work led to the development of mGluR2/3 agonists for both anxiety and schizophrenia. Eli Lilly reported therapeutic effects of LY-544344 for anxiety in GAD patients (Dunayevich et al., 2008) and with LY-2140023 for relief of positive and negative symptoms in schizophrenia (Patil et al., 2007).
To date, most of the available pharmacological tools targeting the mGluR2 receptor have been structural analogues of glutamate and act as orthosteric agonists. While demonstrating proof of principle for use in psychiatric disease, agonists have poor pharmacokinetic profiles and poor brain penetration. Furthermore, several pre-clinical studies have demonstrated tolerance to mGluR2/3 agonists upon repeated dosing in rodents (Cartmell et al., 2000; Galici et al., 2005; Jones et al., 2005). Unlike orthosteric agonists, positive allosteric modulators (PAMs) only activate the receptor when glutamate or another orthosteric agonist is present. Therefore, PAMs are thought to retain spatial and temporal activity of glutamate transmission in the brain and would not continuously stimulate the mGluR2 receptor, potentially avoiding tolerance or unwanted side effects of the agonists. Furthermore, since PAMs bind to an allosteric site on the receptor, they can be designed to be selective for the mGluR2 receptor. Pre-clinical studies and early development of mGluR2 PAMs suggest that they will be effective therapies for positive and negative symptoms and co-morbidy anxiety in schizophrenia.
Based on the expression pattern and functional role of mGluR2, this receptor has emerged as an important target for drug discovery in a number of therapeutic indications. In clinical trials, activating mGluR2 was shown to be efficacious in treating anxiety disorders. In addition, activating mGluR2 has been shown to be efficacious in various animal models of schizophrenia, epilepsy, addiction/drug dependence, Parkinson's disease, pain, sleep disorders, and Huntington's disease. See the following publications: Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia. Mark E Fraley; Expert Opin. Ther. Patents (2009) 19(8); Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice. Galici Ruggero; et al. The Journal of Pharmacology and Experimental Therapeutics (2006), 318(1), 173-85; Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. Krystal, John; et al. CNS Drugs (2010), 24(8), 669-693; Postsynaptic and presynaptic group II metabotropic glutamate receptor activation reduces neuronal excitability; in rat midline paraventricular thalamic nucleus. Hermes M L H J; et al.; The Journal of Pharmacology and Experimental Therapeutics (2011), 336(3), 840-9; Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor. Gary Tresadern, et al.; Bioorganic & Medicinal Chemistry Letters 20 (2010) 175-179; 3-Benzyl-1,3-oxazolidin-2-ones as mGluR2 positive allosteric modulators: Hit-to lead and lead optimization. Allen J. Duplantier, et al.; Bioorganic & Medicinal Chemistry Letters 19 (2009) 2524-2529. Use of mGluR2 PAMs for the treatment of cocaine dependence: Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats. Dhanya, Raveendra-Panickar; et al.; Journal of Medicinal Chemistry (2011), 54(1), 342-353; The mGluR2 Positive Allosteric Modulator BNA Decreases Cocaine Self-Administration and Cue-Induced Cocaine-Seeking and Counteracts Cocaine-Induced Enhancement of Brain Reward Function in Rats. Jin, Xinchun; et al.; Neuropsychopharmacology (2010), 35(10), 2021-2036.
The invention provides technical advantages, for example, the compounds are novel and are ligands for the mGluR2 receptor and may be useful for the treatment of various disorders of the central nervous system. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.